The Clinical Trial of Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic HBV Infection (HBRN Immune Tolerant P) sought to determine the safety and efficacy of treatment using a combination of drugs (entecavir and pegylated interferon) in children ages 3-<18 years old with immunotolerant chronic hepatitis B. Children age 3-<18 years with immunotolerant chronic hepatitis B (CHB) infection who fulfilled the entry criteria received entecavir as monotherapy for 8 weeks and then combination therapy with entecavir and pegylated interferon by weekly subcutaneous injection until week 48. Children were to be followed for 48 weeks after discontinuation of therapy.

The primary objective of the study was to determine whether treatment with 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon leads to an increased rate of sustained virologic response in children with immunotolerant HBV infection, when compared to no treatment, the current standard of care.

The primary outcome measures for evaluation of drug efficacy were HBeAg loss (lack of detectable HBeAg) and HBV DNA levels ≤1,000 IU/mL at 48 weeks following cessation of treatment. The number, type, and rate of adverse or serious events through end of treatment at 48 weeks and end of follow-up at 96 weeks were assessed as the primary outcome measures for safety. Secondary outcome measures, evaluated at 48 and 96 weeks, included hepatitis B surface antigen (HBsAg) loss, hepatitis B e antigen (HBeAg) loss, HBeAg or HBsAg seroconversion, alanine aminotransferase (ALT) levels, HBV DNA levels, and absence of detectable antiviral drug-resistance HBV mutations.

Individuals between the ages of 3 and 18 years who met the following criteria were eligible for the study:

• Documented chronic HBV infection (as evidenced by detection of HBsAg in serum for ≥ 24 weeks prior to baseline; or positive HBsAg and negative anti-HBc IgM within 24 weeks of baseline visit)
• Presence of HBeAg in serum at the last screening visit within 6 weeks of baseline visit
• Serum HBV DNA level >10^7 IU/mL on at least 2 occasions at least 12 weeks apart
• ALT ≤ 60 IU/l in males or ≤40 IU/l in females, measured on at least 2 occasions, at screening (within 6 weeks prior to baseline visit) & at least 12 weeks prior to the screening visit
• Compensated liver disease, with normal total bilirubin (except if Gilbert's syndrome), direct bilirubin ≤0.5 mg/dL, INR ≤1.5, and serum albumin ≥3.5 g/dL
• Creatinine clearance 90 ml/min.
• Absence of hepatocellular carcinoma on liver ultrasound in the past 48 weeks.

Exclusion criteria are documented in the study protocol.

At 48 weeks after treatment ended, 2 children achieved the primary endpoint and were also HBsAg negative and anti–hepatitis B surface antigen antibody (anti-HBs) positive. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs.